The chromosomes of an individual with the Ser270Asn-3 amino acid change have longer and more fragile telomeres than those of a healthy control (C2) group. Longer and more fragile telomeres point to a possible defect in telomere maintenance, which may be involved in melanoma development, according to this study.
Published:
9/4/2014

Researchers, including staff of the Cancer Genomics Research Laboratory (CGR), Leidos Biomedical Research, have recently discovered POT1 as a major susceptibility gene for familial melanoma.

According to the study, which was published in Nature Genetics, approximately 10 percent of cutaneous malignant melanoma cases occur in families. CDKN2A is the most frequent high-risk melanoma susceptibility gene, found in 20–40 percent of familial melanoma cases. However, CDKN2A, along with another gene, CDK4, accounts for only a small proportion of melanoma susceptibility in families.

Using whole-exome sequencing, which targets the portion of the genome that encodes proteins, researchers identified a rare variant that alters the protein in POT1 in five unrelated melanoma-prone families from Romagna, Italy. These five families came from 56 families with melanoma that the research group studied.

“It has only been possible to perform whole-exome sequencing for the past few years,” said Meredith Yeager, Ph.D, senior principal scientist and scientific director of CGR. “For many of the families that we study, we’ve been hunting for their disease genes for decades.”

The study reveals POT1 as a possible underlying genetic factor in familial melanoma cases where the gene causing melanoma is unknown (60–80 percent of cases).

“We hope that adding another telomere-related gene to the list of melanoma genes will help focus research in this area,” Yeager said.

She also noted that POT1 has already been linked to other diseases, such as bone marrow failure syndromes, chronic lymphocytic leukemia, and gastric cancer.

CGR staff members were involved throughout the study, providing support for DNA quantification and staging, project tracking, pre-sequencing quality control (e.g., making sure the samples were from related individuals and were the right sex), and all of the laboratory and analytic work, according to Yeager.

Lead authors on the paper included CGR staff members Michael Cullen, Ph.D., Zhaoming Wang, Ph.D., Xijun Zhang, Ji He, Ph.D., and Yeager. Additional CGR authors were Joseph Boland, Laurie Burdett, Ph.D., Belynda Hicks, Herbert Higson, Amy Hutchinson, Kristine Jones, Sally Larson, Hyo Jung Lee, Michael Malasky, Michelle Manning, Adri O’Neil, and Rebecca Wasser. Sarangan Ravichandran, Ph.D., Advanced Biomedical Computing Center, Information Systems Program, also contributed to the study and paper.

Image: The chromosomes of an individual with the Ser270Asn-3 amino acid change have longer and more fragile telomeres than those of a healthy control (C2) group. Longer and more fragile telomeres point to a possible defect in telomere maintenance, which may be involved in melanoma development, according to this study.

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